The present invention is drawn toward a bioactive agent delivering system that allows for the prolonged and controlled release of a bioactive agent within an in vitro or in vivo environment. More specifically, the present invention comprises a biodegradable gel matrix and a microparticle system wherein the microparticle is embedded in the biodegradable gel matrix, from which the bioactive agent is released in a controlled manner. The bioactive agent may be located within the microparticle only, or within both the microparticle and the gel matrix.
Many biologically active macro-molecules such as peptides/proteins and DNA, effective for gene therapy and a variety of therapeutic applications, have become commercially available through advances in recombinant DNA and other technologies. However, these molecules are limited to parenteral administration due to their susceptibility to degradation in the gastrointestinal tract. Treatment for chronic illnesses or indications may require multiple injections per day over many days, or months. Patient compliance is usually poor. Therefore, it would be highly desirable to develop a system for the delivery of bioactive agents or drugs, in particular, polypeptide or protein drugs, at a controlled rate over a sustained period of time without the above mentioned problems. This system would help to optimize the therapeutic efficacy, minimize the side effects, and thereby improve patient compliance.
Attempts to maintain a steady level of medication using biodegradable polymers have recently attracted considerable attention. These polymers are biodegradable and do not require retrieval after the medication is exhausted. Therefore, they can be fabricated into microspheres, microcapsules or nanospheres with the drug encapsulated within. Various micro-encapsulation techniques incorporating a bio-active agent into a microparticle carrier are taught in the art, e.g. See U.S. Pat. Nos. 4,652,441; 5,100,669; 4,438,253 and 5,665,428.
However, burst release of the drug is often observed immediately after administration of the microparticle delivery system. Release of the agent from a microparticle delivery system comprises an initial burst release from the surface of the device. Much higher than normal therapeutic levels of medication in the blood resulting from the burst effect of a microparticle system can cause side effects such as nausea, vomiting, delirium and, sometimes, death. Similar situations can occur when the polymer matrix is catastrophically eroded. Moreover, microparticle dosage forms are not retrievable should an adverse effect occur.
Therefore, it would be desirable to provide a bio-active agent delivery system that reduces the xe2x80x9cburst releasexe2x80x9d problem by incorporating the microparticle in a biocompatible, environmentally sensitive polymeric gel matrix. As such, the polymer gel would act as a secondary release barrier for the bio-active agent, reducing the effect of burst release. The microparticle-polymer gel bio-agent delivery system of the present invention provides better control of bio-active agent delivery than either the microparticles or the polymeric gel alone would. In addition, since the microparticles are entrapped and localized, retrieval of the microparticel-gel system, if needed, is relatively easy.
It is an object of the present invention to provide a dosage form that comprises a drug containing microparticle delivery system, which is suspended in a gelling solution. Upon administration within the body of a human or other warm-blooded animal the gel sets forming a depot and entrapping therein the drug-containing microparticles.
Another object of the present invention is to provide a controlled drug delivery system for the parenteral administration of hydrophilic and hydrophobic drugs, protein and peptide drugs, and oligo-nucleotides over an extended period.
Yet another object of this invention is to provide a drug delivery system that reduces the xe2x80x9cburstxe2x80x9d effect associated with microparticle delivery systems, improves the bioavailability and duration of action.
It is a further object of the present invention to provide a dosage form that can suspend the microparticles effectively and prevent plugging of hypodermic needles during administration.
Another object of the present invention is to provide a dosage form that localizes the microparticles in a gel depot that is easy to identify and retrieve should surgical removal become necessary or prescribed.
It is another object of the present invention to provide a bio-active agent delivery system that localizes and protects the bio-active agent containing microparticles from enzyme degradation.
It is still another object of the present invention to provide a bio-active agent delivery system that enables the practioner to modulate release of the bio-active agent into the biological environment.
A further object of this invention is to provide a drug delivery system for the parenteral administration of hydrophilic and hydrophobic drugs, peptide and protein drugs, hormones, genes, oligonucleotides and anti-cancer agents.
These and other objects may be accomplished through a bio-active agent delivery system that combines two bio-active agent delivery technologies, namely, microparticle delivery and polymeric gel delivery. The agent delivery system of the present invention comprises a gel matrix and a microparticle system wherein the microparticle system is embedded in the gel matrix. One or more agents to be delivered may be located in the microparticle alone or both in the microparticle and the gel matrix. The microparticle-gel delivery system of the present invention can release the agent over a prolonged period of time, at a relatively constant rate. The release profile of the system can be modified by altering the microparticle and/or the gel composition. The gel solution is surface active and slightly more viscous than normal saline. Therefore, it can be a wetting agent and, at the same time, an excellent suspending agent for microparticles. This suspension can be injected smoothly without clogging while using a relatively small-gauge needle. After injection, the gel sets and localizes the microparticle suspended in it. The agent encapsulated in the microparticle must be released from the microparticle before traveling through the gel matrix and entering the biological system. Therefore, the immediate release, or the burst, associated with microparticle delivery systems can be reduced and modulated. Since the release rates of the agent from these two systems can be quite different, embedding microparticles in the gel phase offers additional modulation and economical use of the agent. The benefits include higher bioavailability and longer duration of action than either system when used alone. Moreover, the combined system can improve the safety of microparticle dosage form. Since the microparticles are localized by the gel they can be surgically retrieved should one decide to terminate the medication delivery for any reason.
Artificial or natural microparticles including microcapsules, microspheres, and nanospheres contain the bio-active agent to be delivered to the body. Any bio-active agent having the ability to be contained and released by these microparticles may be used. The microparticles are then incorporated into a biocompatible polymeric gel that is capable of releasing the microparticles and/or bioactive material within the biological environment, in a controlled manner.
Additional objects and advantages of this invention will become apparent from the following summary and detailed description of the various embodiments making up this invention.